Vitamin C to Decrease Effects of Smoking during Pregnancy on Offspring Airway Function, Airway Size, and Epigenetic Correlates: VCSIP cohort follow-up through 10 Years of Age

项目摘要/摘要 孕妇孕期吸烟导致胎儿肺发育受损，呼吸道功能下降 (用力呼气流量)，以及后代患喘息/哮喘的风险增加。它是一个重要的决定因素 终生下呼吸道功能和更高的呼吸道发病率。在我们的随机对照试验中(“维生素C 为了减少怀孕期间吸烟对婴儿肺功能的影响，我们证明了维生素 与安慰剂相比，补充C的怀孕吸烟者在3岁时的后代有更好的呼吸道功能 12个月，5岁。人类后代之间的这些呼吸道功能的差异 随机化组也随着年龄的增长而增加。我们还发现， 4至6岁时出现喘鸣。在出生前或出生后吸烟暴露方面， 随机分组。所有临床参与者和研究人员仍然对治疗分配视而不见。调解 分析表明，维生素C对喘息的影响主要是由于其对呼吸道功能的影响。干预措施 生命早期是很重要的，因为纵向研究表明，呼吸道功能轨迹已经建立 早期，儿童在下呼吸道功能百分位数往往有持续性地进入下呼吸道功能 成年后，患成人肺部疾病的风险可能会增加。我们的研究是第一次也是唯一的 研究表明，针对已知环境毒素的宫内干预可以产生 在生命早期持续增加的呼吸道功能。这一发现与NHLBI的目标高度相关。 这项建议的目的是继续研究独特的VCSIP研究的后代，以确定 孕期吸烟者产前补充维生素C是否能改善呼吸道运动轨迹 10岁以下儿童的功能和降低呼吸道发病率(具体目标1)。在具体目标2和3中，我们将 检查结构和分子机制，维生素C可能通过这些机制来改变 孕妇孕期吸烟对肺部发育的影响。在特定目标2中，我们将使用低剂量高分辨率 在10岁时进行计算机断层扫描(HRCT)以确定呼吸道大小的增加是否是基础 改善了呼吸道功能。在特定目标3中，评估口腔和血液中DNA甲基化的变化 样本，我们将确定在怀孕和怀孕期间受母亲吸烟影响最大的关键基因和途径 通过补充维生素C进行修饰，以及它们与呼吸道功能的呼吸结果的关系， 呼吸道发病率和呼吸道大小。这些儿童将接受每年一次的口腔呼吸道功能测试。 拭子，头发尼古丁水平，7岁和10岁时的血液，10岁时的低剂量HRCT扫描。这 随访将确定孕期吸烟者补充维生素C是否改善呼吸道功能 和呼吸道发病率进入儿童期中期，确定改善呼吸道功能的机制是否 增加呼吸道大小，并探索可能支持维生素这些有益效果的表观遗传变化 孕期吸烟者的补充剂。

Project Summary/Abstract Maternal smoking during pregnancy leads to impaired fetal lung development, decreased airway function (forced expiratory flows), and an increased risk for wheeze/asthma in the offspring. It is an important determinant of lifelong lower airway function and greater respiratory morbidity. In our randomized controlled trial (“Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function” [VCSIP]), we demonstrated that vitamin C supplementation versus placebo to pregnant smokers resulted in better airway function in the offspring at 3 and 12 months, and at 5 years of age. These differences in airway function between the offspring of the randomized groups also increased with age. We also demonstrated a significant decrease in the occurrence of wheeze at 4 to 6 years of age. There was no difference in prenatal or postnatal smoke exposure between the randomized groups. All clinical participants and investigators remain blinded to treatment allocations. Mediation analysis indicates the effect of vitamin C on wheeze is primarily due to its effect on airway function. Interventions early in life are important as longitudinal studies demonstrate that airway function trajectories are established early, and children in the lower airway function percentiles tend to have persistently lower airway function into adulthood and are likely at increased risk for adult pulmonary disease. Our studies are the first and only studies to show that an in-utero intervention targeted for a known environmental toxin can produce a persistent increase in airway function early in life. This finding is highly relevant to the aims of the NHLBI. The aims of this proposal are to continue to study the offspring from the unique VCSIP study to determine whether prenatal supplementation with vitamin C to pregnant smokers produces an improved trajectory of airway function and lower respiratory morbidity through 10 years of age (specific aim 1). In specific aims 2 and 3 we will examine the structural and molecular mechanisms by which vitamin C may be acting to modify the effects of maternal smoking during pregnancy on lung development. In specific aim 2, we will use low dose high-resolution computed tomography (HRCT) scans done at 10 years of age to determine if increased airway size underlies the improved airway function. In specific aim 3, evaluating DNA methylation changes in serial buccal and blood samples, we will identify critical genes and pathways most affected by maternal smoking during pregnancy and modified by vitamin C supplementation, as well as their association with respiratory outcomes of airway function, respiratory morbidity, and airway size. The children will be studied with yearly airway function tests, buccal swabs, hair for nicotine levels, blood at ages 7 and 10, and a low dose HRCT scan at 10 years of age. This follow-up will determine whether the vitamin C supplementation in pregnant smokers improves airway function and respiratory morbidity into mid-childhood, determine if the mechanism for the improved airway function is increased airway size, and explore the epigenetic changes that may underlie these beneficial effects of vitamin C supplementation for pregnant smokers.